The long range goal of this research project is to develop and optimize image-guided radiofrequency (RF) tumor ablation in patients. The development of minimally-invasive thermal tumor ablation therapies is a major interest of interventional radiologists and is a designated specific interest of the Diagnostic Imaging Program of the NCI, particularly for focal liver lesions, given the morbidity of surgical resection and the large number of inoperable patients. While RF has been successful in ablating small tumors, the extent of tumor destruction obtained has been limited by tissue physiology. This proposal assesses the unique potential of adjuvant, pharmacologic modulation to alter the biologic environment during RF ablation to overcome this barrier. Their preliminary studies in models demonstrate that direct injection or systemic administration of agents that reduce blood flow and/or alter tissue conductivity during RF substantially increases tissue heating and coagulation compared to RF alone. However, further study is required prior to adapting these strategies for clinical practice, as pharmacologic manipulations may exert variable effects on ablation in tumors. Thus, this proposal will have a direct and immediate impact on the future research directions and the clinical implementation of RF tumor ablation. The three hypotheses to be studied include: 1) that RF heating and resultant coagulation correlate inversely with blood flow in tumors; 2) that RF heating and coagulation correlate with tissue conductivity to maximum values and then decrease; and 3) that combined techniques to decrease blood flow and alter tissue conductivity during RF have synergistic effects on tissue heating and coagulation compared to either technique alone. This will be accomplished by: a) characterizing the effects of blood flow on RF ablation efficacy in rabbit VX2 carcinoma and rat R3230 mammary adenocarcinoma tumor models using vasoactive pharmaceuticals; b) characterizing the effects of altering tissue conductivity with pre-treatment saline injection on RF ablation efficacy in R3230 and normal swine liver models; and c) optimizing the combined effects of altered blood flow and tissue conductivity on RF ablation efficacy with directly injected ethanol or acetic acid diluted in saline in the R3230 model; and/or d) combined systemic and injection adjuvant therapies in all three models. RF tissue heating and coagulation will be compared to determine the best method for increasing RF ablation efficacy in each tumor and tissue model.